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Yinkai Duan^1,2, Hao Zhou^1,2, Xiang Liu³

¹Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

|September 11, 2023

概括

通过影响主要蛋白酶 (Mpro) 的突变,SARS-CoV-2 可能会对尼马特里尔病毒产生耐药性. 这些变化要么减少药物结合,要么增强蛋白酶活性,影响病毒适应性和药物疗效.

科学领域:

病毒学
生物化学
药物发现

背景情况:

涅玛特利维尔是针对SARS-CoV-2主要蛋白酶 (Mpro) 的已批准的抗病毒药物,用于COVID-19治疗.
在SARS-CoV-2的高突变率引起了对抗病毒耐药性的担忧.
之前的研究表明基因突变导致耐尼马特利维尔耐药性,但机制尚不清楚.

研究的目的:

阐明SARS-CoV-2对尼尔马特利维尔耐药性的分子机制.
研究Mpro突变如何影响药物结合和蛋白酶活性.
了解恢复病毒健康的补偿机制.

主要方法:

生物化学试验
对14个Mpro突变体的结构生物学研究
对Mpro-药物和Mpro-基质复合物的分析

主要成果:

在S1和S4亚位点的突变降低了涅马特利维尔的结合.
在S2和S4'亚位点的突变增加了Mpro蛋白酶活性.
这些双重机制有助于尼马特里尔维尔耐药性和恢复病毒适应性,也被观察到对恩西特里尔维尔.

结论:

阐明了SARS-CoV-2对Mpro抑制剂耐药性的两个不同的分子机制.
证明突变如何降低药物结合或增加蛋白酶活性,从而导致耐药性.
这些发现为设计下一代Mpro抑制剂以克服耐药性提供了基础.

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